Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang 110016, China.
Shenyang Hinewy Pharmaceutical Technology Co., Ltd., 41 Liutang Road, Shenhe District, Shenyang 110016, China.
J Med Chem. 2020 Dec 24;63(24):15752-15772. doi: 10.1021/acs.jmedchem.0c01524. Epub 2020 Dec 12.
ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y and P2Y on the platelet. The clinical effectiveness of inhibiting P2Y has been well established, and preclinical studies indicated that the inhibition of P2Y could provide equivalent antithrombotic efficacy as P2Y antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1-imidazole scaffold of our previously reported xanthine oxidase inhibitor , we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y and P2Y. We described the structure-activity relationships of the 2-phenyl-1-imidazole compounds, which led to the identification of the most potent antiplatelet agents, and , both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that and could be promising drug candidates.
ADP 介导的血小板聚集通过血小板上的 G 蛋白偶联受体 P2Y 和 P2Y 来信号传递。抑制 P2Y 的临床效果已经得到充分证实，临床前研究表明，抑制 P2Y 可以提供与 P2Y 拮抗剂相当的抗血栓形成效果，并降低出血风险。基于我们之前报道的黄嘌呤氧化酶抑制剂的 2-苯基-1-咪唑骨架，我们首次实现了从黄嘌呤氧化酶抑制剂到针对 P2Y 和 P2Y 的双重靶标拮抗剂的转变。我们描述了 2-苯基-1-咪唑化合物的构效关系，这导致了发现最有效的抗血小板药物 和 ，两者在药代动力学研究中均表现出快速起效。此外，大鼠模型表明 与替格瑞洛相比，具有更宽的治疗窗口，在相同口服剂量下，与替格瑞洛相比，具有等效且剂量依赖性的抗血栓形成效果和更低的出血。这些结果表明 和 可能是有前途的候选药物。
